Prominent role of the Ig-like V domain in trans-interactions of nectins -: Nectin3 and nectin4 bind to the predicted C-C′-C-D β-strands of the nectin1 V domain

Nectins form a family of integral molecules that belong to the immunoglobulin superfamily. Their ectodomain is made of three Ig-like domains (V, C, C). This family comprises at least five members, namely nectin1, -2, -3, -4, and poliovirus receptor (PVR), that are involved in different physiological and pathological processes. W Nectins are adhesion molecules localized at adherens junctions in epithelial cells. (ii) Some nectins act as poliovirus or alpha-herpesvirus receptors (nectin1). (iii) Nectin1 mutations are involved in orofacial developmental abnormalities in humans. Adhesion properties of nectins are mediated by Ca2+-independent homophilic and heterophilic processes through ectodomain trans-interactions. We have described a nectin trans-hetero-interaction network: nectin3 binds to nectin1, nectin2, and PVR; nectin1 also binds to nectin4. In the present study we compared the affinities of the different trans-interactions mediated by, nectin1. We found that the K-D of nectin1/nectin3 and nectin1/nectin4 interactions is I and 100 nm, respectively, whereas the K-D of the nectin1-mediated homophilic interaction is 1 gm. We show that nectin1/nectin3 and nectin1/nectin4 transhetero-interactions were mediated through trans V to V domain interactions, whereas C domains contributed to increase the affinity of the interaction. Nectin3 and nectin4 share a common binding region in the nectin1 V domain: M nectin3 strongly competed with nectin4 binding, (ii) nectin3 and nectin4 binding to nectin1. was reduced by a number of monoclonal antibodies directed against the nectin1 V domain, and (iii.) the glycoprotein D of herpes simplex virus-1 that binds to the V domain of nectin1 reduced nectin3 and nectin4: binding. Finally, using chimeric nectin1/PVR receptors where PVR V domain beta-strands were substituted with the corresponding regions of nectin1, the nectin3 and nectin4 minimal binding region on nectin1 V domain was mapped to the C-C'-C-D beta-strands.